Journal of
Review Article
Vol. 7, No. 1, 1-9 https://doi.org/10.15280/jlm.2017.7.1.1
Lifestyle Medicine
Food and Drug Interactions Jong Hwan Choi1 and Chang Mann Ko2,* Departments of 1Biochemistry and 2Pharmacology, Yonsei University Wonju College of Medicine, Wonju, Korea
Natural foods and vegetal supplements have recently become increasingly popular for their roles in medicine and as staple foods. This has, however, led to the increased risk of interaction between prescribed drugs and the bioactive ingredients contained in these foods. These interactions range from pharmacokinetic interactions (absorption, distribution, metabolism, and excretion influencing blood levels of drugs) to pharmacodynamic interactions (drug effects). In a quantitative respect, these interactions occur mainly during metabolism. In addition to the systemic metabolism that occurs mainly in the liver, recent studies have focused on the metabolism in the gastrointestinal tract endothelium before absorption. Inhibition of metabolism causes an increase in the blood levels of drugs and could have adverse reactions. The food-drug interactions causing increased blood levels of drugs may have beneficial or detrimental therapeutic effects depending on the intensity and predictability of these interactions. It is therefore important to understand the potential interactions between foods and drugs should and the specific outcomes of such interactions. Key Words: Food, Drug, Pharmacodynamic interaction, Pharmacokinetic interaction
INTRODUCTION
food-drug interactions focusing on recent findings. A food– drug interaction is the consequence of a physical, chemical,
Food is one of the most important components of a
or physiologic relationship between a drug and a product con-
healthy lifestyle. Recent studies have focused on the active
sumed as food or a nutrient present in a botanically-derived
role of food products on health and longevity, specifically
food or dietary supplement [1]. The influence of dietary sub-
on preventing cardiovascular and malignant diseases. In this
stances on drug effects depends on numerous variables rang-
regard, the consumption of natural foods and vegetal supple-
ing from physicochemical properties of the drug to host fac-
ments has increased spectacularly over the last few decades
tors such as enzymes and transporters in the gastrointestinal
raising concerns over the potential interactions between food
(GI) tract [2] as well as in the entire body. The interactions
products and drugs particularly in patients undergoing
may affect not only blood levels of drugs through pharmaco-
chronic therapy. Therefore, this review briefly summarizes
kinetic change (absorption, distribution, metabolism and excretion, pharmacokinetic interactions), but also the actual ef-
Received: December 29, 2016, Accepted: January 5, 2017
fects of drugs (pharmacodynamic interactions).
*Corresponding author: Chang Mann Ko Department of Pharmacology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426, Republic of Korea Tel: 82-33-741-0301, Fax: 82-33-742-4966 E-mail: [email protected] This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
PHARMACODYNAMIC INTERACTION Some foods attenuate or enhance drug effects and toxicity by interfering with drug actions, mechanisms and the pharmacodynamics of the drug. Examples of pharmacodynamic interactions are as follows:
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
The anti-coagulant warfarin antagonizes vitamin K1 re-
absorption by delaying gastric emptying, stimulating/in-
cycling leading to the depletion of active vitamin K1.
creasing bile or splanchnic blood flow, increasing/decreasing
However, green leafy vegetables or “greens” contain large
GI pH, or changing the gut flora through mechanical or
amounts of vitamin K1 reversing its depletion. Similarly, re-
physiological mechanisms.
nin-angiotensin system inhibitors increase plasma potassium + [K ] levels due to a reduction in aldosterone activity. + However, foods rich in [K ] such as oranges and bananas
2. Pharmacokinetic interactions related with enzymes and transporters
may cause hyperkalemia resulting in cardiac arrest and
Most of the pharmacokinetic interactions occur when
death due to myocardial arrhythmia. In addition, a hyper-
food alters the activities of the enzymes and/or transporters
tensive crisis can result from the ingestion of tyramine-rich
involved in drug pharmacokinetic processes. To investigate
foods (fermented foods such as wine and cheese) in con-
these pharmacokinetic interactions, the enzymes or trans-
junction with monoamine oxidase inhibitors (MAOIs).
porters involved in the interaction and the active compounds
MAOIs, used to treat depression, inhibit the breakdown of
contained in the food working on them must be clarified.
endogenous and dietary amines. Consequently, MAOIs re-
However, food products contain too many compounds mak-
duce the breakdown of tyramine, a precursor of catechol-
ing it difficult to investigate all of them. Consequently, most
amines (endogenous vasoconstrictors), and raise catechol-
studies focused firstly on the phytochemicals contained in
amine biosynthesis causing a hypertensive crisis [3].
the dietary supplements consumed for health, such as natu-
All these pharmacokinetic interactions of food and drug
ral food, vegetal extracts, and commonly consumed fruit
are relatively easy to predict and are recognized and exam-
juices, teas, and alcoholic drinks. A number of studies have
ined during the drug development stage.
investigated the effects of phytochemicals on drug metabolism. It has however been challenging to conclusively
PHARMACOKINETIC INTERACTION
indicate the effect of phytochemicals on drug metabolism because of the discrepancies observed between in vitro and
Pharmacokinetic interactions cause an increase or de-
in vivo studies [7]. The results obtained in vitro have fre-
crease in the blood levels of drugs and therefore, their ef-
quently failed to be replicated in vivo probably because of
fects and toxicities.
the following reasons: (1) insufficient concentration(s) of
1. Pharmacokinetic interactions caused by physicochemical properties The physiochemical properties of food products may
causative ingredients at the enzyme or transporter active site, (2) metabolism of causative ingredients to inactive products, or (3) transport of causative ingredients out of target cells (e.g., enterocytes and hepatocytes) [8].
cause changes in the pharmacokinetics of drugs by chemi-
Recent reports have shown that dietary substances elicit
cally binding to the drug and converting it into an insoluble
a significant influence on drug absorption particularly in the
salt that is not easily absorbed. For example, proteins in the
GI tract, the primary portal for drugs and dietary
food would bind to the antiepileptic agent, phenytoin, re-
substances. In this case, dietary substances do not have to
sulting in reduced phenytoin absorption and potentially in-
be taken up by the body and therefore do not undergo
adequate seizure control [4]. Some tetracyclines and fluo-
metabolism. Attention is drawn to the modulation of the
roquinolones can bind to divalent cation-containing products
metabolizing enzymes, as well as uptake and efflux trans-
(e.g., calcium in dairy) resulting in reduced drug absorption
porters located particularly in the GI tract [9]. Inhibition of
and potential therapeutic failure [5].
metabolism and active efflux in the GI tract would be ex-
On the other hand, foods rich in fat can increase drug
pected to increase systemic drug exposure enhancing the ef-
absorption by improving the solubility of lipid soluble drugs,
fect and toxicity of drugs while the inhibition of active up-
such as some antiretroviral protease inhibitors (e.g., saquina-
take would produce a completely opposite result. Many phy-
vir and atazanavir) [6]. Food products may also affect drug
tochemicals have been shown to inhibit these processes held
2
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
in the GI tract in vitro. However, clinical applications re-
molecules including drugs in the body.
main insignificant or undetermined. More details are discussed below regarding metabolic en-
1) P-glycoprotein
zymes and transporters, and the actual influences on drug
P-glycoprotein (P-gp) is a membrane protein that protects
actions mediated by the enzymes and/or transporters af-
cells by extruding toxic/unknown substances from cells.
fected by actual dietary substances.
P-gp is highly expressed in tissues that have direct contact
3. Metabolizing enzymes and presence in the GI enterocyte
with xenobiotics such as the epithelium of the gastro-intestinal tract (the polarized apical membranes of enterocytes), the renal proximal tubule (at the brush border lev-
1) Cytochrome P450
el), the canalicular surface of hepatocytes, and the endothe-
Cytochrome P450s are a superfamily of enzymes
lial cell surface of the blood brain barrier [14,15]. Cancer
(encoded by the gene CYP) involved in the phase 1 metabo-
cells can often develop resistance not only to anti-cancer
lism of xenobiotics and endogenous compounds [10]. The
agents which they have been exposed to, but also to other
3 families of CYP1, CYP2, and CYP3, and CYP3A4,
drugs and chemicals that they have yet to come in contact
CYP1A2, and CYP2C9 from these families constitute the
with [15]. Some dietary supplements have a major influence
major liver enzymes in the human body. The prevalence of
on P-glycoprotein-mediated transport, thus interfering with
these enzymes in human hepatic smooth endoplasmic retic-
anti-cancer therapies.
ulum is as follows: CYP3A4 (30%), CYP2C9 (20%),
In the GI tract, P-gp is also expressed on the apical
CYP1A2 (13%), CYP2E1 (7%), CYP2A6 (4%), CYP2D6
(luminal) membrane of enterocytes where drugs are pump-
(2%), and CYP2B6 (1%) [11].
ed back into the intestinal lumen, lowering the systemic
CYP3A4 is also a major CYP located in the villous tips
drug concentration [16]. It can therefore be postulated that
of the enterocytes lining the duodenum to the distal
the inhibition of enteric P-gp may increase systemic drug
jejunum. These destroy drugs before they reach the sys-
exposure. However, it has been difficult to establish an in
temic circulation (pre-systemic metabolism, a sort of first
vivo model to study intestinal P-gp largely because an ideal
pass metabolism). CYP3A is responsible for the oxidative
P-gp probe substrate has not been identified and several
metabolism of more than half of the pharmaceutical agents
drugs transported by P-gp are also metabolized by CYP3A
on the market [12].
[17]. Therefore, it remains to be seen whether the increase in serum levels of CYP3A/P-gp substrates that occur after
2) Esterase
ingestion of dietary substances that inhibit both CYP3A and
Esterases are enzymes that metabolize inactive biological
P-gp has an effect on CYP3A and P-gp individually or
compounds, known as prodrugs, to their active form in the
both.
body through hydrolytic cleavage of the ester bond to form the active species. Inhibition of enteric esterase activity by
2) Organic anion transporting polypeptide
dietary substances in rats has been shown to increase stabil-
In contrast to P-pg, organic anion transporting poly-
ity of the ester in the lumen and enterocytes, resulting in
peptides (OATPs), a type of transmembrane transport pro-
higher absorption of the ester and higher exposure to active
tein, facilitate the uptake of a number of endogenous com-
metabolites via rapid hydrolysis in the plasma [13]. The
pounds (e.g., bile acids, hormones) and drugs [18]. Of the
clinical significance of esterase inhibition by dietary sub-
11 human OATP family members, OATP1A2 and
stances remains under investigation.
OATP2B1 have been reported to be expressed on the apical
4. Transporters and Presence in the GI enterocytes Several types of transporters (transporting proteins) are involved in the absorption and distribution of macro-
membranes of enterocytes [19]. A decrease in the drug concentration in systemic circulation could be attributed to the inhibition
of
an
apically
located
intestinal
transporter.
3
uptake
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
PHARMACOKINETIC INTERACTIONS OF ACTUAL DIETARY SUPPLEMENTS 1. Grapefruit juice
anocoumarins (e.g., 6',7'-dihydroxybergamottin, bergamottin), in aggregate, have been established as the major mediators of the ‘GFJ effect’ in humans. Modes of intestinal CYP3A inhibition include reversible and mecha-
Juice prepared from grapefruit (Citrus × paradisi
nism-based processes as well as degradation of the protein
Macfad.) is one of the most extensively studied dietary sub-
[26]. Similar effects were noted in several fruit juices in ex-
stances shown to inhibit CYP3A. Ingredients of grapefruit
tensive studies held in vitro and in human participants.
juice (GFJ) such as flavonoids, naringenin, and apigenin are
It has also been demonstrated in vitro that GFJ flavonoids
reported to inhibit the liver enzymes CYP3A4 and CYP1A2
have esterase inhibitory activity and this concept provides
[20]. Since CYP3A is located in the liver as well as in the
an explanation of their plausible mechanism of interaction
intestine, GFJ may influence its drug metabolism process in
with ester prodrugs [27]. However, contributions of these
both sites. The main difference between these two inter-
effects in patients are not significant in the interactions of
actions would lie in the changes in the half life (T1/2) of
GFJ with drugs.
the blood concentration of the drug. The inhibition of hep-
GFJ also acts on drug transporter proteins (such as P-gp)
atic metabolism in the liver would increase T1/2, but in-
at the intestinal level. Unfortunately, however, it also in-
hibition at the intestine would cause no change.
hibits hepatic P-gp, without affecting the activity of liver
Co-administration of GFJ (250 mL daily for more than
CYP3A4 [28]. Some of the flavonoid compounds present in
three months) with the anticancer drug docetaxel was re-
grapefruit (quercetin and naringenin) also inhibit trans-
ported to cause dermatologic toxicity in a patient. Two
porter proteins of organic cations (OCT) and organic anion
weeks after stopping GFJ administration, the area under the
transporters (OAT) from the basal membrane of intestinal
curve (AUC) in the blood concentration of docetaxel de-
epithelium [29].
creased by 60% with T1/2 acceleration and the adverse re-
There are several reports demonstrating the inhibition of
action disappeared [21]. In another case study, the admin-
OATP at the intestinal level. GFJ significantly reduced the
istration of amiodarone, an anti-arrhythmic drug, to a pa-
mean AUC of aliskiren, a direct renin inhibitor, by 61%
tient who regularly consumed GFJ (≥1-1.5 L/day) resulted
with no observable change in half-life, consistent with the
in a marked QT prolongation associated with ventricular ar-
inhibition of intestinal but not hepatic OATPs in 11 healthy
rhythmia including an episode of torsade de pointes [22].
volunteers who were administered GFJ (200 mL sin-
These two case reports are in line with previous findings
gle-strength three times daily for five days) and aliskiren
that GFJ inhibits hepatic and intestinal cytochrome P450
(150 mg on day 3) [30]. Similarly, the mean AUC decreased
enzymes, in particular CYP3A. Bailey et al. [23] also in-
by 38% after GFJ in healthy subjects receiving 300 mg alis-
dicated that GFJ inhibits the drug pre-systemic metabolism
kiren and either water or GFJ (300 mL) [31]. In these cases,
mediated by CYP, particularly the isoform CYP3A4 in the
the average IC50 was well below the reported range of con-
bowel. On the other hand, Kupferschmidt et al. [24] did not
centrations in grapefruit juice [31]. The clinical significance
observe any significant changes on the half-life of either
of the SLCO2B1*3 polymorphism has also been demon-
orally or intravenously administered midazolam in a patient
strated in patients with asthma receiving the leukotriene re-
drinking GFJ regularly. Compelling evidence, therefore, in-
ceptor antagonist montelukast in adults [32] and children
dicates that GFJ indeed enhances systemic drug exposure by
[33]. Unfortunately, the results regarding the influence of
inhibiting CYP3A mediated pre-systemic (first-pass) metab-
GFJ on the drug transporters (P-gp, OCT, and OAT) are
olism in the intestine without changing T1/2 [25].
premature, and larger trials are needed to demonstrate re-
The inhibition of CYP3A4 may be induced after consum-
producibility of the clinical observations.
ing 200-300 mL of GFJ, while the effect of increasing the
The most important drugs mentioned in the literature that
bioavailability and toxicity of the drugs may occur in the
interact with GFJ in terms of adverse events are calcium
first 24 hours after consumption. Compounds known as fur-
channel blockers (amlodipine, felodipine, manidipine, ni-
4
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
cardipine, nifedipine, nimodipine, nisoldipine, nitrendipine,
1) Red wine
pranidipine, etc.), angiotensin II receptor blockers (losartan),
There have been many studies investigating the inter-
beta-blockers (talinolol and acebutolol), some antiar-
actions between red wine, made from the common grape
rhythmic drugs (amiodarone, quinidine, disopyramide, and
(Vitis vinifera L.), and clinical drugs. However, the findings
propafenone), anti-cancer agents (vinblastine), and some
from the studies have been inconsistent or clinically insig-
statins (atorvastatin) [10,34,35]. The increase in systemic
nificant [41]. The magnitude of the effect of red wine on
drug exposure can be sufficient to produce adverse events
the pharmacokinetics of CYP3A substrates may depend on
such as muscle pain with some statins and severe hypo-
both the amount and type of red wine consumed.
tension with some calcium channel blockers.
Differentiating the effects of ethanol and wine components
Focusing on the adverse events of drugs, it is the current
also poses a challenge. The red wine components, trans-re-
medical recommendation that individuals avoid grapefruit
sveratrol and gallic acid, have been shown to inhibit hepatic
juice consumption while taking these types of drugs. Very
CYP3A in vitro in a mechanism-based and non-competitive,
recently, however, questions have been asked as to whether
reversible manner, respectively. However, enteric inhibition
GFJ should be recommended rather than avoided [36] based
by red wine remains to be clearly elucidated [42].
on a report by Lee et al. [37]. Lee et al. [37] demonstrated that GFJ increased the blood levels of simvastatin and lova-
2) Beer
statin by about 260% and hence enhanced their therapeutic
Beer contains many types of phenolic acids and pren-
effects by reducing LDL cholesterol levels by 37% and is-
yl-flavonoids, some of which are used primarily for flavor-
chemic heart disease risk by 61%. The report indicated that
ing and preserving beer [43]. An evaluation of the in-
increments in rhabdomyolysis risk after GFJ consumption
hibitory effects of a wide range of ales, lagers, specialty
were minimal compared to the greater benefit of preventing
beers, ciders, and non-alcoholic lagers on CYP systems
heart disease caused by statins. The report therefore sug-
showed that some beers induced the inhibition of
gested that GFJ juice should probably not be contra-
CYP3A4-mediated metabolism by up to 78%. However,
indicated in people taking statins.
there were wide variations in alcohol and hop acids contents.
As described above, there is compelling evidence that in-
As a result, a definitive relationship between inhibition and
teractions between drugs and GFJ may have potential ther-
hops constituent levels could not be established [44].
apeutic benefits. However, more studies are needed to over-
Further studies with individual compounds are warranted to
come the challenges hindering the exploration of these ben-
support the clinical evaluation.
eficial therapeutic effects such as the uncertainty regarding their intensity and interaction predictability [36]. 2. Alcoholic beverages
3) Tea Tea is the most widely consumed beverage in the world, second only to water. The processing technique for the
Growing evidence supporting the cardio-protective bene-
leaves of the tea plant (Camellia sinensis (L.) Kuntze) dic-
fits of alcoholic beverages has promoted moderate alcohol
tates the level of fermentation and type of tea — white,
consumption as part of a healthy lifestyle. Alcoholic drinks
green, black, oolong, etc. [45]. Green tea undergoes minimal
such as wine and beer are rich in flavonoids and other poly-
oxidation during processing, ensuring high polyphenol con-
phenols that have antioxidant properties [38] and can alter
tent [46]. The predominant polyphenolic compounds are
CYP activity through mechanisms that are independent of
catechins, which are presumed to prevent and/or treat can-
ethanol [39]. However, data on enteric CYP3A inhibition
cer, cardiovascular disease, and obesity [47]. The majority
by teas and alcoholic beverages (e.g., wine, beer) are less
of controlled clinical studies evaluating the effect of re-
abundant and their clinical significance remains to be de-
peated green tea administration (given as an extract) on
termined [40].
CYP activity have failed to demonstrate clinically significant interactions to date [48].
5
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
Green tea has gathered attention due to its potential ef-
ficial functions: one example being epigallocatechin gallate
fects on OATPs. Green tea contains catechins including epi-
which reduces O2 to yield H2O2 to promote apoptosis and
gallocatechin gallate (EGCG), epicatechin (EC), epi-
exert cytotoxic activity against bacteria [60].
gallocatechin (EGC), and epicatechin gallate (ECG) in high
Flavonoid pro-oxidant functions could have potentially
concentrations. In vitro studies have shown that both EGCG
toxic effects. Some individual flavonoids, for example quer-
and ECG inhibited both OATP2B1- or OATP1A2-mediated
cetin, particularly at high-dose levels, are able to induce
estrone-3-sulfate uptake by ~70% and ~75%, respectively
toxic effects, including pro-oxidant activity, which could be
[49]. Interestingly, their concentrations (IC50 ＜ 100 μM)
related to mutagenicity and mitochondrial toxicity. For ex-
were much lower than the concentrations in typical green
ample, quercetin efficiently protects against H2O2- induced
tea (average ~450 μM). Consumption of a cup (e.g.
DNA damage in rat lung epithelial (RLE) cells, but this
240-300 mL) or two of green tea would result in intestinal
protection results in a reduction in GSH levels, an increase
concentrations of ECG and EGCG within the range that in-
in LDH leakage, and an increase in cytosolic free calcium
hibits OATP activity. However, no clinical studies have re-
concentration [61]. Ultimately, quercetin acts as a toxicant.
ported on the significance of intestinal OATP inhibition by
This phenomenon has been defined as “the quercetin para-
green tea except for several case reports on rats [50] and
dox” (the conversion of quercetin into a potential toxicant
humans [51]. Again, larger clinical studies are needed to de-
while offering protection by scavenging ROS) [61,62]. It is
termine the clinical significance of these observations.
surmised that oxidized quercetin is generated intensely in subjects with elevated oxidative stress associated with patho-
POLYPHENOLS: ANTIOXIDANTS BECOMING PRO-OXIDANTS
logical conditions (diabetes mellitus, obesity, malignancies, etc.). In the event that these subjects have low levels of GSH, quercetin used for antioxidant reactions may become
Antioxidant activity of polyphenols or flavonoids is be-
toxic making them even more susceptible to damage by
lieved to be the central mechanism involved in the health
quercetin oxidation metabolites [52,61]. However, this kind
promoting effects of natural foods and vegetal supplements
of toxicity would require very high concentrations (＞sev-
[52-54]. Flavonoids are natural polyphenols, best known as
eral hundreds of mM) [63,64], indicating that quercetin use
pigments responsible for a diversity of colors found in vege-
is indeed rather safe [65]. The extent to which flavonoids
tables (yellow, orange, red, etc.—their name being derived
are able to act as anti- or pro-oxidants in vivo is still poorly
from the Latin word flavus meaning yellow).
understood [59].
There are some problematic issues that are linked to the
Subjects usually consuming a rich polyphenols diet are
use of vegetal supplements and vegetal components of diet,
characterized by concentrations of respective compounds
especially when associated with classical medicines. Several
ranging between 2.5 and 10 μM. Subjects using natural
reports revealed the possibility of pro-oxidant effects in-
supplements can reach blood levels of over 20 μM poly-
duced by polyphenols, which were generally known for
phenols [66-68].
their antioxidant effects. We should be aware that flavonoids (like many other antioxidants), can act, under certain circumstances, as pro-oxidants, for example in systems
CONCLUSION
containing redox-active metals (copper, iron, etc.) [55]. The
Interactions between drugs and food products occur in
pro-oxidant activity is linked to the total number of hydrox-
various ways and in various steps ranging from ingestion,
yl groups in a flavonoid molecule. As the total number in-
absorption, metabolism, and excretion of both the drug and
creases, the hydroxyl groups increase the risk for production
food product. Some of the effects induced by food-drug in-
of radical/nonradical reactive species (hydrogen peroxide
teractions, such as an increase in the blood drug level, may
and hydroxyl radicals) in Fenton reactions [56-59]. The fla-
have potential therapeutic benefits while some interactions
vonoid pro-oxidant function could be related to their bene-
may result in detrimental physiological effects. It is there-
6
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
fore important to understand and examine the potential interactions between foods and drugs and their specific effects at an individual level.
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OATP2B1 and CYP3A4 substrate aliskiren. Clin Pharmacol Ther 2010;88:339-42. Rebello S, Zhao S, Hariry S, Dahlke M, Alexander N, Vapurcuyan A, Hanna I, Jarugula V. Intestinal OATP1A2 inhibition as a potential mechanism for the effect of grapefruit juice on aliskiren pharmacokinetics in healthy subjects. Eur J Clin Pharmacol 2012;68: 697-708. Mougey EB, Feng H, Castro M, Irvin CG, Lima JJ. Absorption of montelukast is transporter mediated: a common variant of OATP2B1 is associated with reduced plasma concentrations and poor response. Pharmacogenet Genomics 2009;19:129-38. Mougey EB, Lang JE, Wen X, Lima JJ. Effect of citrus juice and SLCO2B1 genotype on the pharmacokinetics of montelukast. J Clin Pharmacol 2011;51:751-60. Ofer M, Wolffram S, Koggel A, Spahn-Langguth H, Langguth P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur J Pharm Sci 2005;25:263-71. Owira PM, Ojewole JA. The grapefruit: an old wine in a new glass? Metabolic and cardiovascular perspectives. Cardiovasc J Afr 2010;21:280-5. Wang Y, Klass E. Grapefruit with Your Statin? Am J Med 2016;129:e159. Lee JW, Morris JK, Wald NJ. Grapefruit juice and statins. Am J Med 2016;129:26-9. Krenz M, Korthuis RJ. Moderate ethanol ingestion and cardiovascular protection: from epidemiologic associations to cellular mechanisms. J Mol Cell Cardiol 2012;52:93-104. Jang GR, Harris RZ. Drug interactions involving ethanol and alcoholic beverages. Expert Opin Drug Metab Toxicol 2007;3:719-31. Huang SM, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, Abraham S, Habet SA, Baweja RK, Burckart GJ, Chung S, Colangelo P, Frucht D, Green MD, Hepp P, et al. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters, and the guidance process. J Clin Pharmacol 2008;48:662-70. Bailey D. Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3a4 activity: comparison with grapefruit juice. Clin Pharmacol Ther 2003;73: 529-37. Stupans L, Tan HW, Kirlich A, Tuck K, Hayball P, Murray M. Inhibition of CYP3A-mediated oxidation in human hepatic microsomes by the dietary derived complex phenol, gallic acid. J Pharm Pharmacol 2002;54: 269-75. Huvaere K, Andersen ML, Olsen K, Skibsted LH, Heyerick A, De Keukeleire D. Radicaloid-type oxidative decomposition of beer bittering agents revealed.
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Chemistry (Easton) 2003;9:4693-9. 44. Foster BC, Arnason JT, Saleem A, Tam TW, Liu R, Mao J, Desjardins S. Comparative study of hops-containing products on human cytochrome P450-mediated metabolism. J Agric Food Chem 2011;59:5159-63. 45. Sang S, Lambert JD, Ho CT, Yang CS. The chemistry and biotransformation of tea constituents. Pharmacol Res 2011;64:87-99. 46. Colalto C. Herbal interactions on absorption of drugs: Mechanisms of action and clinical risk assessment. Pharmacol Res 2010;62:207-27. 47. Antonello M, Montemurro D, Bolognesi M, Di Pascoli M, Piva A, Grego F, Sticchi D, Giuliani L, Garbisa S, Rossi GP. Prevention of hypertension, cardiovascular damage and endothelial dysfunction with green tea extracts. Am J Hypertens 2007;20:1321-8. 48. Chow HH, Hakim IA, Vining DR, Crowell JA, Cordova CA, Chew WM, Xu MJ, Hsu CH, Ranger-Moore J, Alberts DS. Effects of repeated green tea catechin administration on human cytochrome P450 activity. Cancer Epidemiol Biomarkers Prev 2006;15:2473-6. 49. Roth M, Timmermann BN, Hagenbuch B. Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos 2011;39:920-6. 50. Qiao J, Gu C, Shang W, Du J, Yin W, Zhu M, Wang W, Han M, Lu W. Effect of green tea on pharmacokinetics of 5-fluorouracil in rats and pharmacodynamics in human cell lines in vitro. Food Chem Toxicol 2011;49: 1410-5. 51. Vischini G, Niscola P, Stefoni A, Farneti F. Increased plasma levels of tacrolimus after ingestion of green tea. Am J Kidney Dis 2011;58:329. 52. Boots AW, Haenen GR, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol 2008;585:325-37. 53. Spanou CI, Veskoukis AS, Stagos D, Liadaki K, Aligiannis N, Angelis A, Skaltsounis A-L, Anastasiadi M, Haroutounian SA, Kouretas D. Effects of Greek legume plant extracts on xanthine oxidase, catalase and superoxide dismutase activities. J Physiol Biochem 2012;68:37-45. 54. Stagos D, Portesis N, Spanou C, Mossialos D, Aligiannis N, Chaita E, Panagoulis C, Reri E, Skaltsounis L, Tsatsakis AM, Kouretas D. Correlation of total polyphenolic content with antioxidant and antibacterial activity of 24 extracts from Greek domestic Lamiaceae species. Food Chem Toxicol 2012;50:4115-24. 55. Margina D, Ilie M, Gradinaru D, Androutsopoulos VP, Kouretas D, Tsatsakis AM. Natural products-friends or foes? Toxicol Lett 2015;236:154-67. 56. Cao G, Sofic E, Prior RL. Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships. Free Radic Biol Med 1997;22:749-60.
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57. Hanasaki Y, Ogawa S, Fukui S. The correlation between active oxygens scavenging and antioxidative effects of flavonoids. Free Radic Biol Med 1994;16:845-50. 58. Heim KE, Tagliaferro AR, Bobilya DJ. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J Nutr Biochem 2002;13:572-84. 59. Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011;82:513-23. 60. Nakagawa H, Hasumi K, Woo JT, Nagai K, Wachi M. Generation of hydrogen peroxide primarily contributes to the induction of Fe(II)-dependent apoptosis in Jurkat cells by (-)-epigallocatechin gallate. Carcinogenesis 2004;25:1567-74. 61. Boots AW, Li H, Schins RP, Duffin R, Heemskerk JW, Bast A, Haenen GR. The quercetin paradox. Toxicol Appl Pharmacol 2007;222:89-96. 62. Jacobs H, Moalin M, Bast A, van der Vijgh WJ, Haenen GR. An essential difference between the flavonoids monoHER and quercetin in their interplay with the endogenous antioxidant network. PLoS One 2010;5: e13880. 63. Wilms LC, Kleinjans JCS, Moonen EJC, Briedé JJ. Discriminative protection against hydroxyl and superoxide anion radicals by quercetin in human leucocytes in vitro. Toxicol In Vitro 2008;22:301-7.
64. Yen GC, Duh PD, Tsai HL, Huang SL. Pro-oxidative Properties of Flavonoids in Human Lymphocytes. Biosci Biotechnol Biochem 2003;67:1215-22. 65. Harwood M, Danielewska-Nikiel B, Borzelleca JF, Flamm GW, Williams GM, Lines TC. A critical review of the data related to the safety of quercetin and lack of evidence of in vivo toxicity, including lack of genotoxic/carcinogenic properties. Food Chem Toxicol 2007; 45:2179-205. 66. Margina D, Gradinaru D, Manda G, Neagoe I, Ilie M. Membranar effects exerted in vitro by polyphenols – quercetin, epigallocatechin gallate and curcumin – on HUVEC and Jurkat cells, relevant for diabetes mellitus. Food Chem Toxicol 2013;61:86-93. 67. Tribolo S, Lodi F, Connor C, Suri S, Wilson VG, Taylor MA, Needs PW, Kroon PA, Hughes DA. Comparative effects of quercetin and its predominant human metabolites on adhesion molecule expression in activated human vascular endothelial cells. Atherosclerosis 2008; 197:50-6. 68. Winterbone MS, Tribolo S, Needs PW, Kroon PA, Hughes DA. Physiologically relevant metabolites of quercetin have no effect on adhesion molecule or chemokine expression in human vascular smooth muscle cells. Atherosclerosis 2009;202:431-8.
9
Review Article
Vol. 7, No. 1, 1-9 https://doi.org/10.15280/jlm.2017.7.1.1
Lifestyle Medicine
Food and Drug Interactions Jong Hwan Choi1 and Chang Mann Ko2,* Departments of 1Biochemistry and 2Pharmacology, Yonsei University Wonju College of Medicine, Wonju, Korea
Natural foods and vegetal supplements have recently become increasingly popular for their roles in medicine and as staple foods. This has, however, led to the increased risk of interaction between prescribed drugs and the bioactive ingredients contained in these foods. These interactions range from pharmacokinetic interactions (absorption, distribution, metabolism, and excretion influencing blood levels of drugs) to pharmacodynamic interactions (drug effects). In a quantitative respect, these interactions occur mainly during metabolism. In addition to the systemic metabolism that occurs mainly in the liver, recent studies have focused on the metabolism in the gastrointestinal tract endothelium before absorption. Inhibition of metabolism causes an increase in the blood levels of drugs and could have adverse reactions. The food-drug interactions causing increased blood levels of drugs may have beneficial or detrimental therapeutic effects depending on the intensity and predictability of these interactions. It is therefore important to understand the potential interactions between foods and drugs should and the specific outcomes of such interactions. Key Words: Food, Drug, Pharmacodynamic interaction, Pharmacokinetic interaction
INTRODUCTION
food-drug interactions focusing on recent findings. A food– drug interaction is the consequence of a physical, chemical,
Food is one of the most important components of a
or physiologic relationship between a drug and a product con-
healthy lifestyle. Recent studies have focused on the active
sumed as food or a nutrient present in a botanically-derived
role of food products on health and longevity, specifically
food or dietary supplement [1]. The influence of dietary sub-
on preventing cardiovascular and malignant diseases. In this
stances on drug effects depends on numerous variables rang-
regard, the consumption of natural foods and vegetal supple-
ing from physicochemical properties of the drug to host fac-
ments has increased spectacularly over the last few decades
tors such as enzymes and transporters in the gastrointestinal
raising concerns over the potential interactions between food
(GI) tract [2] as well as in the entire body. The interactions
products and drugs particularly in patients undergoing
may affect not only blood levels of drugs through pharmaco-
chronic therapy. Therefore, this review briefly summarizes
kinetic change (absorption, distribution, metabolism and excretion, pharmacokinetic interactions), but also the actual ef-
Received: December 29, 2016, Accepted: January 5, 2017
fects of drugs (pharmacodynamic interactions).
*Corresponding author: Chang Mann Ko Department of Pharmacology, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426, Republic of Korea Tel: 82-33-741-0301, Fax: 82-33-742-4966 E-mail: [email protected] This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
PHARMACODYNAMIC INTERACTION Some foods attenuate or enhance drug effects and toxicity by interfering with drug actions, mechanisms and the pharmacodynamics of the drug. Examples of pharmacodynamic interactions are as follows:
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
The anti-coagulant warfarin antagonizes vitamin K1 re-
absorption by delaying gastric emptying, stimulating/in-
cycling leading to the depletion of active vitamin K1.
creasing bile or splanchnic blood flow, increasing/decreasing
However, green leafy vegetables or “greens” contain large
GI pH, or changing the gut flora through mechanical or
amounts of vitamin K1 reversing its depletion. Similarly, re-
physiological mechanisms.
nin-angiotensin system inhibitors increase plasma potassium + [K ] levels due to a reduction in aldosterone activity. + However, foods rich in [K ] such as oranges and bananas
2. Pharmacokinetic interactions related with enzymes and transporters
may cause hyperkalemia resulting in cardiac arrest and
Most of the pharmacokinetic interactions occur when
death due to myocardial arrhythmia. In addition, a hyper-
food alters the activities of the enzymes and/or transporters
tensive crisis can result from the ingestion of tyramine-rich
involved in drug pharmacokinetic processes. To investigate
foods (fermented foods such as wine and cheese) in con-
these pharmacokinetic interactions, the enzymes or trans-
junction with monoamine oxidase inhibitors (MAOIs).
porters involved in the interaction and the active compounds
MAOIs, used to treat depression, inhibit the breakdown of
contained in the food working on them must be clarified.
endogenous and dietary amines. Consequently, MAOIs re-
However, food products contain too many compounds mak-
duce the breakdown of tyramine, a precursor of catechol-
ing it difficult to investigate all of them. Consequently, most
amines (endogenous vasoconstrictors), and raise catechol-
studies focused firstly on the phytochemicals contained in
amine biosynthesis causing a hypertensive crisis [3].
the dietary supplements consumed for health, such as natu-
All these pharmacokinetic interactions of food and drug
ral food, vegetal extracts, and commonly consumed fruit
are relatively easy to predict and are recognized and exam-
juices, teas, and alcoholic drinks. A number of studies have
ined during the drug development stage.
investigated the effects of phytochemicals on drug metabolism. It has however been challenging to conclusively
PHARMACOKINETIC INTERACTION
indicate the effect of phytochemicals on drug metabolism because of the discrepancies observed between in vitro and
Pharmacokinetic interactions cause an increase or de-
in vivo studies [7]. The results obtained in vitro have fre-
crease in the blood levels of drugs and therefore, their ef-
quently failed to be replicated in vivo probably because of
fects and toxicities.
the following reasons: (1) insufficient concentration(s) of
1. Pharmacokinetic interactions caused by physicochemical properties The physiochemical properties of food products may
causative ingredients at the enzyme or transporter active site, (2) metabolism of causative ingredients to inactive products, or (3) transport of causative ingredients out of target cells (e.g., enterocytes and hepatocytes) [8].
cause changes in the pharmacokinetics of drugs by chemi-
Recent reports have shown that dietary substances elicit
cally binding to the drug and converting it into an insoluble
a significant influence on drug absorption particularly in the
salt that is not easily absorbed. For example, proteins in the
GI tract, the primary portal for drugs and dietary
food would bind to the antiepileptic agent, phenytoin, re-
substances. In this case, dietary substances do not have to
sulting in reduced phenytoin absorption and potentially in-
be taken up by the body and therefore do not undergo
adequate seizure control [4]. Some tetracyclines and fluo-
metabolism. Attention is drawn to the modulation of the
roquinolones can bind to divalent cation-containing products
metabolizing enzymes, as well as uptake and efflux trans-
(e.g., calcium in dairy) resulting in reduced drug absorption
porters located particularly in the GI tract [9]. Inhibition of
and potential therapeutic failure [5].
metabolism and active efflux in the GI tract would be ex-
On the other hand, foods rich in fat can increase drug
pected to increase systemic drug exposure enhancing the ef-
absorption by improving the solubility of lipid soluble drugs,
fect and toxicity of drugs while the inhibition of active up-
such as some antiretroviral protease inhibitors (e.g., saquina-
take would produce a completely opposite result. Many phy-
vir and atazanavir) [6]. Food products may also affect drug
tochemicals have been shown to inhibit these processes held
2
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
in the GI tract in vitro. However, clinical applications re-
molecules including drugs in the body.
main insignificant or undetermined. More details are discussed below regarding metabolic en-
1) P-glycoprotein
zymes and transporters, and the actual influences on drug
P-glycoprotein (P-gp) is a membrane protein that protects
actions mediated by the enzymes and/or transporters af-
cells by extruding toxic/unknown substances from cells.
fected by actual dietary substances.
P-gp is highly expressed in tissues that have direct contact
3. Metabolizing enzymes and presence in the GI enterocyte
with xenobiotics such as the epithelium of the gastro-intestinal tract (the polarized apical membranes of enterocytes), the renal proximal tubule (at the brush border lev-
1) Cytochrome P450
el), the canalicular surface of hepatocytes, and the endothe-
Cytochrome P450s are a superfamily of enzymes
lial cell surface of the blood brain barrier [14,15]. Cancer
(encoded by the gene CYP) involved in the phase 1 metabo-
cells can often develop resistance not only to anti-cancer
lism of xenobiotics and endogenous compounds [10]. The
agents which they have been exposed to, but also to other
3 families of CYP1, CYP2, and CYP3, and CYP3A4,
drugs and chemicals that they have yet to come in contact
CYP1A2, and CYP2C9 from these families constitute the
with [15]. Some dietary supplements have a major influence
major liver enzymes in the human body. The prevalence of
on P-glycoprotein-mediated transport, thus interfering with
these enzymes in human hepatic smooth endoplasmic retic-
anti-cancer therapies.
ulum is as follows: CYP3A4 (30%), CYP2C9 (20%),
In the GI tract, P-gp is also expressed on the apical
CYP1A2 (13%), CYP2E1 (7%), CYP2A6 (4%), CYP2D6
(luminal) membrane of enterocytes where drugs are pump-
(2%), and CYP2B6 (1%) [11].
ed back into the intestinal lumen, lowering the systemic
CYP3A4 is also a major CYP located in the villous tips
drug concentration [16]. It can therefore be postulated that
of the enterocytes lining the duodenum to the distal
the inhibition of enteric P-gp may increase systemic drug
jejunum. These destroy drugs before they reach the sys-
exposure. However, it has been difficult to establish an in
temic circulation (pre-systemic metabolism, a sort of first
vivo model to study intestinal P-gp largely because an ideal
pass metabolism). CYP3A is responsible for the oxidative
P-gp probe substrate has not been identified and several
metabolism of more than half of the pharmaceutical agents
drugs transported by P-gp are also metabolized by CYP3A
on the market [12].
[17]. Therefore, it remains to be seen whether the increase in serum levels of CYP3A/P-gp substrates that occur after
2) Esterase
ingestion of dietary substances that inhibit both CYP3A and
Esterases are enzymes that metabolize inactive biological
P-gp has an effect on CYP3A and P-gp individually or
compounds, known as prodrugs, to their active form in the
both.
body through hydrolytic cleavage of the ester bond to form the active species. Inhibition of enteric esterase activity by
2) Organic anion transporting polypeptide
dietary substances in rats has been shown to increase stabil-
In contrast to P-pg, organic anion transporting poly-
ity of the ester in the lumen and enterocytes, resulting in
peptides (OATPs), a type of transmembrane transport pro-
higher absorption of the ester and higher exposure to active
tein, facilitate the uptake of a number of endogenous com-
metabolites via rapid hydrolysis in the plasma [13]. The
pounds (e.g., bile acids, hormones) and drugs [18]. Of the
clinical significance of esterase inhibition by dietary sub-
11 human OATP family members, OATP1A2 and
stances remains under investigation.
OATP2B1 have been reported to be expressed on the apical
4. Transporters and Presence in the GI enterocytes Several types of transporters (transporting proteins) are involved in the absorption and distribution of macro-
membranes of enterocytes [19]. A decrease in the drug concentration in systemic circulation could be attributed to the inhibition
of
an
apically
located
intestinal
transporter.
3
uptake
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
PHARMACOKINETIC INTERACTIONS OF ACTUAL DIETARY SUPPLEMENTS 1. Grapefruit juice
anocoumarins (e.g., 6',7'-dihydroxybergamottin, bergamottin), in aggregate, have been established as the major mediators of the ‘GFJ effect’ in humans. Modes of intestinal CYP3A inhibition include reversible and mecha-
Juice prepared from grapefruit (Citrus × paradisi
nism-based processes as well as degradation of the protein
Macfad.) is one of the most extensively studied dietary sub-
[26]. Similar effects were noted in several fruit juices in ex-
stances shown to inhibit CYP3A. Ingredients of grapefruit
tensive studies held in vitro and in human participants.
juice (GFJ) such as flavonoids, naringenin, and apigenin are
It has also been demonstrated in vitro that GFJ flavonoids
reported to inhibit the liver enzymes CYP3A4 and CYP1A2
have esterase inhibitory activity and this concept provides
[20]. Since CYP3A is located in the liver as well as in the
an explanation of their plausible mechanism of interaction
intestine, GFJ may influence its drug metabolism process in
with ester prodrugs [27]. However, contributions of these
both sites. The main difference between these two inter-
effects in patients are not significant in the interactions of
actions would lie in the changes in the half life (T1/2) of
GFJ with drugs.
the blood concentration of the drug. The inhibition of hep-
GFJ also acts on drug transporter proteins (such as P-gp)
atic metabolism in the liver would increase T1/2, but in-
at the intestinal level. Unfortunately, however, it also in-
hibition at the intestine would cause no change.
hibits hepatic P-gp, without affecting the activity of liver
Co-administration of GFJ (250 mL daily for more than
CYP3A4 [28]. Some of the flavonoid compounds present in
three months) with the anticancer drug docetaxel was re-
grapefruit (quercetin and naringenin) also inhibit trans-
ported to cause dermatologic toxicity in a patient. Two
porter proteins of organic cations (OCT) and organic anion
weeks after stopping GFJ administration, the area under the
transporters (OAT) from the basal membrane of intestinal
curve (AUC) in the blood concentration of docetaxel de-
epithelium [29].
creased by 60% with T1/2 acceleration and the adverse re-
There are several reports demonstrating the inhibition of
action disappeared [21]. In another case study, the admin-
OATP at the intestinal level. GFJ significantly reduced the
istration of amiodarone, an anti-arrhythmic drug, to a pa-
mean AUC of aliskiren, a direct renin inhibitor, by 61%
tient who regularly consumed GFJ (≥1-1.5 L/day) resulted
with no observable change in half-life, consistent with the
in a marked QT prolongation associated with ventricular ar-
inhibition of intestinal but not hepatic OATPs in 11 healthy
rhythmia including an episode of torsade de pointes [22].
volunteers who were administered GFJ (200 mL sin-
These two case reports are in line with previous findings
gle-strength three times daily for five days) and aliskiren
that GFJ inhibits hepatic and intestinal cytochrome P450
(150 mg on day 3) [30]. Similarly, the mean AUC decreased
enzymes, in particular CYP3A. Bailey et al. [23] also in-
by 38% after GFJ in healthy subjects receiving 300 mg alis-
dicated that GFJ inhibits the drug pre-systemic metabolism
kiren and either water or GFJ (300 mL) [31]. In these cases,
mediated by CYP, particularly the isoform CYP3A4 in the
the average IC50 was well below the reported range of con-
bowel. On the other hand, Kupferschmidt et al. [24] did not
centrations in grapefruit juice [31]. The clinical significance
observe any significant changes on the half-life of either
of the SLCO2B1*3 polymorphism has also been demon-
orally or intravenously administered midazolam in a patient
strated in patients with asthma receiving the leukotriene re-
drinking GFJ regularly. Compelling evidence, therefore, in-
ceptor antagonist montelukast in adults [32] and children
dicates that GFJ indeed enhances systemic drug exposure by
[33]. Unfortunately, the results regarding the influence of
inhibiting CYP3A mediated pre-systemic (first-pass) metab-
GFJ on the drug transporters (P-gp, OCT, and OAT) are
olism in the intestine without changing T1/2 [25].
premature, and larger trials are needed to demonstrate re-
The inhibition of CYP3A4 may be induced after consum-
producibility of the clinical observations.
ing 200-300 mL of GFJ, while the effect of increasing the
The most important drugs mentioned in the literature that
bioavailability and toxicity of the drugs may occur in the
interact with GFJ in terms of adverse events are calcium
first 24 hours after consumption. Compounds known as fur-
channel blockers (amlodipine, felodipine, manidipine, ni-
4
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
cardipine, nifedipine, nimodipine, nisoldipine, nitrendipine,
1) Red wine
pranidipine, etc.), angiotensin II receptor blockers (losartan),
There have been many studies investigating the inter-
beta-blockers (talinolol and acebutolol), some antiar-
actions between red wine, made from the common grape
rhythmic drugs (amiodarone, quinidine, disopyramide, and
(Vitis vinifera L.), and clinical drugs. However, the findings
propafenone), anti-cancer agents (vinblastine), and some
from the studies have been inconsistent or clinically insig-
statins (atorvastatin) [10,34,35]. The increase in systemic
nificant [41]. The magnitude of the effect of red wine on
drug exposure can be sufficient to produce adverse events
the pharmacokinetics of CYP3A substrates may depend on
such as muscle pain with some statins and severe hypo-
both the amount and type of red wine consumed.
tension with some calcium channel blockers.
Differentiating the effects of ethanol and wine components
Focusing on the adverse events of drugs, it is the current
also poses a challenge. The red wine components, trans-re-
medical recommendation that individuals avoid grapefruit
sveratrol and gallic acid, have been shown to inhibit hepatic
juice consumption while taking these types of drugs. Very
CYP3A in vitro in a mechanism-based and non-competitive,
recently, however, questions have been asked as to whether
reversible manner, respectively. However, enteric inhibition
GFJ should be recommended rather than avoided [36] based
by red wine remains to be clearly elucidated [42].
on a report by Lee et al. [37]. Lee et al. [37] demonstrated that GFJ increased the blood levels of simvastatin and lova-
2) Beer
statin by about 260% and hence enhanced their therapeutic
Beer contains many types of phenolic acids and pren-
effects by reducing LDL cholesterol levels by 37% and is-
yl-flavonoids, some of which are used primarily for flavor-
chemic heart disease risk by 61%. The report indicated that
ing and preserving beer [43]. An evaluation of the in-
increments in rhabdomyolysis risk after GFJ consumption
hibitory effects of a wide range of ales, lagers, specialty
were minimal compared to the greater benefit of preventing
beers, ciders, and non-alcoholic lagers on CYP systems
heart disease caused by statins. The report therefore sug-
showed that some beers induced the inhibition of
gested that GFJ juice should probably not be contra-
CYP3A4-mediated metabolism by up to 78%. However,
indicated in people taking statins.
there were wide variations in alcohol and hop acids contents.
As described above, there is compelling evidence that in-
As a result, a definitive relationship between inhibition and
teractions between drugs and GFJ may have potential ther-
hops constituent levels could not be established [44].
apeutic benefits. However, more studies are needed to over-
Further studies with individual compounds are warranted to
come the challenges hindering the exploration of these ben-
support the clinical evaluation.
eficial therapeutic effects such as the uncertainty regarding their intensity and interaction predictability [36]. 2. Alcoholic beverages
3) Tea Tea is the most widely consumed beverage in the world, second only to water. The processing technique for the
Growing evidence supporting the cardio-protective bene-
leaves of the tea plant (Camellia sinensis (L.) Kuntze) dic-
fits of alcoholic beverages has promoted moderate alcohol
tates the level of fermentation and type of tea — white,
consumption as part of a healthy lifestyle. Alcoholic drinks
green, black, oolong, etc. [45]. Green tea undergoes minimal
such as wine and beer are rich in flavonoids and other poly-
oxidation during processing, ensuring high polyphenol con-
phenols that have antioxidant properties [38] and can alter
tent [46]. The predominant polyphenolic compounds are
CYP activity through mechanisms that are independent of
catechins, which are presumed to prevent and/or treat can-
ethanol [39]. However, data on enteric CYP3A inhibition
cer, cardiovascular disease, and obesity [47]. The majority
by teas and alcoholic beverages (e.g., wine, beer) are less
of controlled clinical studies evaluating the effect of re-
abundant and their clinical significance remains to be de-
peated green tea administration (given as an extract) on
termined [40].
CYP activity have failed to demonstrate clinically significant interactions to date [48].
5
Journal of Lifestyle Medicine Vol. 7, No. 1, January 2017
Green tea has gathered attention due to its potential ef-
ficial functions: one example being epigallocatechin gallate
fects on OATPs. Green tea contains catechins including epi-
which reduces O2 to yield H2O2 to promote apoptosis and
gallocatechin gallate (EGCG), epicatechin (EC), epi-
exert cytotoxic activity against bacteria [60].
gallocatechin (EGC), and epicatechin gallate (ECG) in high
Flavonoid pro-oxidant functions could have potentially
concentrations. In vitro studies have shown that both EGCG
toxic effects. Some individual flavonoids, for example quer-
and ECG inhibited both OATP2B1- or OATP1A2-mediated
cetin, particularly at high-dose levels, are able to induce
estrone-3-sulfate uptake by ~70% and ~75%, respectively
toxic effects, including pro-oxidant activity, which could be
[49]. Interestingly, their concentrations (IC50 ＜ 100 μM)
related to mutagenicity and mitochondrial toxicity. For ex-
were much lower than the concentrations in typical green
ample, quercetin efficiently protects against H2O2- induced
tea (average ~450 μM). Consumption of a cup (e.g.
DNA damage in rat lung epithelial (RLE) cells, but this
240-300 mL) or two of green tea would result in intestinal
protection results in a reduction in GSH levels, an increase
concentrations of ECG and EGCG within the range that in-
in LDH leakage, and an increase in cytosolic free calcium
hibits OATP activity. However, no clinical studies have re-
concentration [61]. Ultimately, quercetin acts as a toxicant.
ported on the significance of intestinal OATP inhibition by
This phenomenon has been defined as “the quercetin para-
green tea except for several case reports on rats [50] and
dox” (the conversion of quercetin into a potential toxicant
humans [51]. Again, larger clinical studies are needed to de-
while offering protection by scavenging ROS) [61,62]. It is
termine the clinical significance of these observations.
surmised that oxidized quercetin is generated intensely in subjects with elevated oxidative stress associated with patho-
POLYPHENOLS: ANTIOXIDANTS BECOMING PRO-OXIDANTS
logical conditions (diabetes mellitus, obesity, malignancies, etc.). In the event that these subjects have low levels of GSH, quercetin used for antioxidant reactions may become
Antioxidant activity of polyphenols or flavonoids is be-
toxic making them even more susceptible to damage by
lieved to be the central mechanism involved in the health
quercetin oxidation metabolites [52,61]. However, this kind
promoting effects of natural foods and vegetal supplements
of toxicity would require very high concentrations (＞sev-
[52-54]. Flavonoids are natural polyphenols, best known as
eral hundreds of mM) [63,64], indicating that quercetin use
pigments responsible for a diversity of colors found in vege-
is indeed rather safe [65]. The extent to which flavonoids
tables (yellow, orange, red, etc.—their name being derived
are able to act as anti- or pro-oxidants in vivo is still poorly
from the Latin word flavus meaning yellow).
understood [59].
There are some problematic issues that are linked to the
Subjects usually consuming a rich polyphenols diet are
use of vegetal supplements and vegetal components of diet,
characterized by concentrations of respective compounds
especially when associated with classical medicines. Several
ranging between 2.5 and 10 μM. Subjects using natural
reports revealed the possibility of pro-oxidant effects in-
supplements can reach blood levels of over 20 μM poly-
duced by polyphenols, which were generally known for
phenols [66-68].
their antioxidant effects. We should be aware that flavonoids (like many other antioxidants), can act, under certain circumstances, as pro-oxidants, for example in systems
CONCLUSION
containing redox-active metals (copper, iron, etc.) [55]. The
Interactions between drugs and food products occur in
pro-oxidant activity is linked to the total number of hydrox-
various ways and in various steps ranging from ingestion,
yl groups in a flavonoid molecule. As the total number in-
absorption, metabolism, and excretion of both the drug and
creases, the hydroxyl groups increase the risk for production
food product. Some of the effects induced by food-drug in-
of radical/nonradical reactive species (hydrogen peroxide
teractions, such as an increase in the blood drug level, may
and hydroxyl radicals) in Fenton reactions [56-59]. The fla-
have potential therapeutic benefits while some interactions
vonoid pro-oxidant function could be related to their bene-
may result in detrimental physiological effects. It is there-
6
Jong Hwan Choi and Chang Mann Ko : Food and Drug Interactions
fore important to understand and examine the potential interactions between foods and drugs and their specific effects at an individual level.
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